APPL1, an adaptor protein containing a PH domain, PTB domain, and leucine zipper motif, is a multifunctional endosomal signaling adaptor. It localizes to Rab5-positive endosomes and coordinates signaling pathways through interactions with many receptors and proteins. APPL1 is central in adiponectin and insulin signaling pathways, which are crucial for regulating glucose and lipid metabolism, energy homeostasis, and are associated with various physiological and pathological processes [1,2,4].

In mouse models, APPL1 has shown to prevent diabetes, endothelial disorders, and insulin resistance. For instance, APPL1 deficiency can lead to metabolic and vascular disorders, highlighting its role in maintaining normal physiological functions [1]. In neurons, over-expressing human APPL1 in transgenic mice (Thy1-APPL1 mice) leads to enlarged neuronal early endosomes, increased synaptic endocytosis, and pathological consequences like hippocampal LTP and LTD changes, cholinergic neuron degeneration, and memory impairment, indicating its role in endosomal and synaptic function [3]. In macrophages, deletion of APPL1 impairs mitophagy, leading to NLRP3 inflammasome over-activation, and APPL1-deficient mice in hematopoietic cells are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation, and glucose dysregulation [5]. Also, APPL1 knockdown in 3T3-L1 cells blocks adipogenic differentiation and promotes adipocyte lipolysis, showing its role in adipocyte biology [6].

In conclusion, APPL1 is essential for normal physiological functions, especially in metabolism-related signaling pathways. Gene-knockout and transgenic mouse models have revealed its role in diseases such as diabetes, neurodegenerative diseases, and inflammation-related disorders, providing insights into potential therapeutic strategies for these conditions.

References:

1. Artimani, Tayebe, Najafi, Rezvan. 2020. APPL1 as an important regulator of insulin and adiponectin-signaling pathways in the PCOS: A narrative review. In Cell biology international, 44, 1577-1587. doi:10.1002/cbin.11367. https://pubmed.ncbi.nlm.nih.gov/32339379/

2. Diggins, Nicole L, Webb, Donna J. . APPL1 is a multifunctional endosomal signaling adaptor protein. In Biochemical Society transactions, 45, 771-779. doi:10.1042/BST20160191. https://pubmed.ncbi.nlm.nih.gov/28620038/

3. Jiang, Ying, Sachdeva, Kuldeep, Goulbourne, Chris N, Mathews, Paul M, Nixon, Ralph A. 2024. Increased neuronal expression of the early endosomal adaptor APPL1 leads to endosomal and synaptic dysfunction with cholinergic neurodegeneration. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.09.19.613736. https://pubmed.ncbi.nlm.nih.gov/39345644/

4. Deepa, Sathyaseelan S, Dong, Lily Q. 2008. APPL1: role in adiponectin signaling and beyond. In American journal of physiology. Endocrinology and metabolism, 296, E22-36. doi:10.1152/ajpendo.90731.2008. https://pubmed.ncbi.nlm.nih.gov/18854421/

5. Wu, Kelvin Ka Lok, Long, KeKao, Lin, Huige, Xu, Aimin, Cheng, Kenneth King Yip. 2021. The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages. In Nature communications, 12, 6637. doi:10.1038/s41467-021-26987-1. https://pubmed.ncbi.nlm.nih.gov/34789781/

6. Wen, Zhongyuan, Tang, Zhao, Li, Mingxin, Fu, Yalin, Wang, Changhua. 2020. APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte lipolysis. In Molecular and cellular endocrinology, 506, 110755. doi:10.1016/j.mce.2020.110755. https://pubmed.ncbi.nlm.nih.gov/32045627/